Our previous research demonstrates that insufficient copper (Cu) during perinatal development has a major impact on the central nervous system leading to severe long-term neurochemical and behavioral consequences. The broad long-range goal of this research is to identify the neurochemical roles for Cu which will lead to a better understanding of the elusive mechanisms of Cu deficient neuropathology. Our ongoing research in rodents demonstrates that there are selected regional neurochemical alterations induced by Cu deficiency including changes in Cu levels, catecholamine pools, and altered activity of cuproenzymes. Our research also suggests that restoration of brain Cu following perinatal deficiency may be difficult, if not impossible. More importantly, we have been able to show that at least one sensory-motor function, acoustic startle, is exquisitely altered in Cu-repleted rats even after months of nutritional supplementation. The specific aims of this focused multidisciplinary project are both descriptive and mechanism based. AIM 1: Firstly, we wish to establish the critical time period and dietary Cu level necessary for expression of permanent behavior alterations and neuropathology. To accomplish these goals, experiments will be conducted using Sprague Dawley rats. Dietary Cu deficiency will be produced during perinatal development and post lactation to investigate nutrition-related responses in the developing nervous system. In all cases, the Cu-deficient or Cu-repleted rats will be compared to Cu-adequate control animals. AIM 2: Secondly, we will identify the mechanism(s) for impaired brain development. Specifically, we will test the hypothesis that low brain norepinephrine is responsible for the altered brain development (hypomyelination and delayed synaptogenesis) and altered auditory startle by including studies with L-3,4-dihydroxyphenylserine (L-DOPS) to bypass the Cu-dependent enzyme dopamine-beta-monooxygenase. Biochemical and behavioral endpoints will be employed. AIM 3: Thirdly, we will identify the mechanism(s) for neuronal pathology. These experiments are based on the hypothesis that necrosis and apoptosis are driven by alterations in brain mitochondrial function. We will study isolated mitochondria and test specific hypotheses related to mechanisms of apoptosis and necrosis. Collectively, accomplishment of these aims will lead to a better understanding of the molecular mechanisms of Cu and are relevant because failure to accumulate Cu during brain development may lead to permanent alterations in neurotransmission, abnormal behavior, and diminished cognitive capacity.